Our laboratory has been studying the effects of the adrenal cortical steroid, dehydroepiandrosterone (DHEA) and DHEA analogs for many years. DHEA treatment of laboratory mice and rats inhibits spontaneous and chemically induced tumorigenesis and increases the mean and maximal lifespan. Reducing the food intake of laboratory rodents also markedly inhibits cancer development and delays the rate of aging. The mechanism of the protective effect of underfeeding is not known. We have developed the hypothesis, based on work in our laboratory and that of others, that overproduction of adrenal cortical steroids (specifically DHEA and corticosterone) is important in mediating the beneficial effects of food restriction. The purpose of this grant proposal is to perform further experiments to test this hypothesis. We will determine if adrenalectomy reverses the food restriction-induced inhibition in 7,12-dimethylbenz(a)anthracene (DMBA)-induced lung adenoma formation in A/J mice. We will determine if adrenalectomy reverses the tumor suppressing effect of food restriction in another species, the rat. We will use the 1,2-dimethylhydrazine (1,2-DMH) induced colon tumor and DMBA-induced mammary tumor models, both of which are very responsive to the tumor-suppressive effect of underfeeding. A primary objective of this research proposal is to determine if underfeeding produces biochemical effects in the mouse epidermis similar to those produced by DHEA treatment and if adrenalectomy reverses these effects. Using the mouse epidermis as a target tissue, we have obtained considerable evidence that DHEA blocks tumor promotion through the inhibition of glucose-6-phosphate dehydrogenase (G6PDH), with a consequent lowering of the NADPH and ribose 5-phosphate cellular pools and inhibition in deoxyribonucleotide synthesis and cell proliferation. We will determine if the depression in epidermal G6PDH activity following food restriction is reversed by adrenalectomy. We will also determine if food restriction lowers the pool sizes of 6-phosphogluconate and other pentose-phosphate pathway intermediates in mouse epidermis and the effect of adrenalectomy on these levels. We will also determine the effect of food restriction, with or without prior adrenalectomy, on the NADP+/NADPH levels in mouse epidermis. We will also determine if deoxyribonucleoside administration significantly overcomes food restriction-induced inhibition in TPA promotion of skin papillomas. A reversing effect of deoxyribonucleoside administration would suggest that depletion of deoxyribonucleotide pool sizes is important to both the tumor inhibiting effect of food restriction and DHEA treatment and would indicate a role for DHEA or a DHEA-like steroid in mediating the tumor inhibitory effect of food restriction.